Severe Obesity Evidence for a Deranged Metabolic

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Severe Obesity: Evidence for a Deranged MetabolicProgram in Skeletal Muscle?Joseph A. Houmard1,2,3, Walter J. Pories3,4, and G. Lynis Dohm3,5

1Department of Kinesiology and 2Human Performance Laboratory, College of Health and Human Performance,East Carolina University, Greenville, NC; 3East Carolina Diabetes and Obesity Center; and 4Departments ofSurgery and 5Physiology, Brody School of Medicine, East Carolina University, Greenville, NC

HOUMARD, J.A., W.J. PORIES, and G.L. DOHM. Severe obesity: evidence for a deranged metabolic program in skeletal

muscle? Exerc. Sport Sci. Rev., Vol. 40, No. 4, pp. 204Y210, 2012. Severe obesity is increasing at a disproportionate rate compared with

milder grade obesity. Our research group has obtained evidence indicative of an obesity metabolic program in skeletal muscles of

severely obese individuals, which may be determined genetically or epigenetically. We believe that this represents a paradigm shift in thinking

about metabolic regulation in obesity. Key Words: bariatric surgery, exercise training, fat oxidation, Class III obesity, insulin action,mitochondria, obesity

INTRODUCTION

Obesity is a chronic disease that is increasing at epidemicproportions. Our research group has been studying skeletalmuscle metabolism in severely obese patients for more than25 yr. These studies were possible initially because of collabo-rating surgeons providing abdominal muscle (rectus abdominus)biopsies that were examined in muscle strip preparations.These in vitro incubation studies were complimented with ex-periments using needle biopsies of a leg muscle (vastus lateralis)

and skeletal muscle cell cultures derived from the tissue oflean and severely obese donors (11,26). In these preparations,we have observed a consistent metabolic profile in severelyobese individuals (body mass index (BMI), Q40 kgImY2), whichhas led us to hypothesize that a constitutive obesity metabolicprogram that contributes to a positive lipid balance andinsulin resistance is involved. This review will focus on ourfindings implicating the existence of a metabolic program inskeletal muscles of severely obese individuals.

THE METABOLIC PROFILE OF THE SKELETALMUSCLE OF SEVERELY OBESE INDIVIDUALS

Fat Metabolism

To determine if a reduction in fatty acid oxidation (FAO)in skeletal muscles was evident with obesity, we measured the

rate of production of labeled carbon dioxide (14CO2) from14C-labeled palmitate as an index of fat oxidation in rectusabdominus muscle strips (27). To our surprise, FAO did notdiffer between the muscles of lean (BMI, 23.8 T 0.6 kgImY2)and obese (BMI, 30.2 T 0.8 kgImY2) individuals but onlyexhibited a significant reduction (60%) in tissue fromseverely obese (BMI, 53.8 T 0.4 kgImY2) subjects (27). Sim-ilarly, in needle biopsies from the vastus lateralis, FAO (14C-labeled palmitate) was reduced by approximately 60% withsevere obesity (3,29). These congruent findings in two muscle

groups were suggestive of a relatively global defect because thetissues sampled were from distinct anatomical areas (abdominalvs leg) with differing functions and recruitment patterns (i.e.,postural (rectus) vs locomotion (vastus)). We feel that theseconsistent findings (3,27,29) provide strong evidence for areduction in FAO in skeletal muscles of severely obese indi-viduals. These data are summarized in Figure 1.

Our subsequent research focused on identifying cellularmechanisms that could contribute to this reduction in FAO.Proteome analyses revealed an increase in glycolytic enzymecontent that was hypothesized to reflect a metabolic shift towardglycolytic energy production to compensate for the decrementin FAO with severe obesity (24). In support, we reported thatthe ratio of phosphofructokinase to citrate synthase enzyme

activities, a surrogate for muscle glycolytic capacity, was elevatedin skeletal muscles of severely obese subjects (29). We also ob-served an elevated generation of lactate from incubated musclestrips, again suggesting an overall metabolic shift (17).

To examine processes involved in FAO directly, musclebiopsy samples were incubated with distinct fatty acids tostudy the carnitine-mediated transport of fatty acids into themitochondria at carnitine palmitoyltransferase 1 (CPT-1) anddownstream (29). With severe obesity, long-chain (palmitate)oxidation was depressed in conjunction with CPT-1 activity,

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ARTICLE

Address for correspondence: Joseph A. Houmard, Ph.D., Human Performance

Laboratory, Ward Sports Medicine Building, East Carolina University, Greenville, NC

27858 (E-mail: [email protected]).Accepted for publication: April 5, 2012.Associate Editor: Donald R. Dengel, Ph.D., FACSM

0091-6331/4004/204 Y210Exercise and Sport Sciences ReviewsCopyright * 2012 by the American College of Sports Medicine

Copyright 2012 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.


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indicating a possible defect at this step (29). However, theoxidation of palmitoyl carnitine, which enters the mitochon-dria independently of CPT-1, also was depressed, indicatingthat processes subsequent to CPT-1, such as A-oxidationand/or the tricarboxylic acid cycle (TCA), also contribute to thereduction in FAO. In support of this tenant, citrate synthase(a TCA cycle enzyme) and A-hydroxyacyl-CoA dehydro-genase (an enzyme involved with A-oxidation) activitieswere lower in the muscles of severely obese individuals (29).These findings are suggestive of a relatively encompassingmetabolic program in skeletal muscles of severely obese indi-viduals, where multiple processes are affected with a resultantdecrement in FAO.

As indicated by these data, the metabolic program withsevere obesity generally involves decrements in oxidative andincreases in glycolytic metabolism. We also have reportedthat skeletal muscles of severely obese individuals are com-

posed of a lower percentage of Type I muscle fibers (22,33).Type I, or red, muscle fibers typically are insulin sensitive andfavor oxidative metabolism compared with Type II (white)muscle fibers; in support, insulin action in our strip prepara-tion was related positively to the percentage of Type I musclefibers (22). This predominance of Type II fibers with severeobesity is again suggestive of a phenotype that favors a lowcapacity for lipid oxidation and insulin resistance. However,it is important to note that fiber type, as determined by histo-chemical staining for myosin adenosine triphosphataseactivity (22,33), may not always reflect specific metabolicprocesses. For example, we have reported that muscle fibertype is not altered in severely obese subjects after the sub-stantial weight loss induced by gastric bypass surgery despite

a marked improvement in insulin action (20,25). Suchfindings indicate that contractile (i.e., fiber type) and met-abolic characteristics may not always be congruent.

Insulin Action

We and others have reported that severely obese individ-uals have whole-body insulin resistance (32). Skeletal mus-cles comprise approximately 45% of body mass in a normalperson and are responsible for approximately 75% of the

glucose disposal after a meal. Therefore, it was reasonable toinvestigate mechanisms of insulin resistance in human muscles.

Using the muscle fiber strip preparation (14), we foundthat glucose transport was stimulated approximately 2.5-foldby insulin in tissue from lean controls, but there was little orno stimulation of glucose transport in muscles from severelyobese patients either with or without type 2 diabetes. Glucose

transport in muscles of severely obese patients, both diabeticand nondiabetic, also was resistant to the action of insulin-likegrowth factor 1 (13). Cumulative data demonstrated that glu-cose transport was stimulated by approximately threefold tofourfold for individuals with a BMI of 20 kgImY2 or less, butthere was a progressive decline in insulin responsiveness inindividuals with a BMI of about 30 kgImY2, after which therevirtually was no insulin-induced stimulation (16). In addi-tion to glucose transport, insulin stimulation of glycogenformation, glucose oxidation, and nonoxidized glycolysis alsowere depressed in muscles of severely obese patients (10).Lactate release was not stimulated by insulin, but basal (ab-sence of insulin) lactate release was much higher in obese thannonobese controls, suggesting a preferential utilization of car-bohydrate as a fuel source (17).

Muscle contraction stimulates glucose transport in a man-ner similar to insulin, that is, translocation of glucose trans-porters to the cell membrane. Thus, we asked the questionwhether muscles from obese individuals also were resistantto stimulation by muscle contraction. In obese Zucker rats,muscle contraction stimulated glucose transport normally, al-though there was severe insulin resistance (15). We were notable to make human muscle fiber strips contract but did ob-serve that hypoxia and vanadate, two stimuli that are believedto function through pathways also activated by muscle con-traction, stimulated glucose transport normally in muscle stripsfrom severely obese insulin-resistant individuals (1,9). Fromthese data, we concluded that the mechanism for the trans-location of the insulin-sensitive glucose transporter (GLUT4)

was functional and the defect must be upstream and within thesignaling pathway, leading to insulin-mediated glucose trans-port. To investigate the effects of obesity on insulin signaltransduction, we again used the muscle fiber strip preparationin the presence and absence of insulin. Insulin stimulation ofinsulin receptor and insulin receptor substrate 1 (IRS-1) tyro-sine phosphorylation and activation of phosphatidylinositol 3-kinase and Akt (also known as protein kinase B) were reducedsubstantially with severe obesity (8,19).

To investigate differences in the insulin signaling pathwayin severely obese subjects, we partially purified insulin recep-tors from biopsy tissue and found that the insulin receptors ofseverely obese subjects had lower tyrosine kinase activity thanthose of nonobese controls (10). When the insulin receptors

from muscles of obese individuals were treated with a serinephosphatase, the tyrosine kinase activity was restored to nor-mal. This suggests that insulin receptors are highly serinephosphorylated in muscles of severely obese individuals, andthis inhibits activity, which is restored when the phosphateis removed (28,35). Phosphorylation of the insulin receptorand IRS-1 on tyrosine residues activates the signaling path-way, whereas serine phosphorylation inhibits signal trans-duction. IRS-1 from muscles of severely obese patients alsowas found to be hyperphosphorylated, especially on serine

Figure 1. Decrement in fatty acid oxidation (FAO) using various meth-odologies with severe obesity in skeletal muscle and inability of weightloss (Weight Reduced columns) to restore FAO. Only exercise training inseverely obese individuals whohave lost weightappears to be effectiveforincreasing FAO. Rectus Adom, rectus abdominus muscle; HSkMC, humanskeletal muscle cells raised in culture. FAO for the columns titled VastusLateralis and Weight Reduced + Exercise were determined in biopsysamples with the muscle homogenate technique.

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312, which would inhibit activity (4). These changes in serinephosphorylation were accompanied by increased activitiesof several serine kinases, including protein kinase C (PKC)(28,35). PKC is activated by diacylglycerol, which is one ofthe lipids stored muscles of obese individuals. The involve-ment of PKC also was implicated by the finding that insulinresistance could be induced by a phorbol ester, which acti-

vates PKC, and insulin sensitivity restored in obese muscleswith a PKC inhibitor (12). Based on these findings, ourhypothesis is that several kinases are activated in muscles ofseverely obese individuals with subsequent serine phos-phorylation of the insulin receptor and IRS-1, which in turnreduces activity. These modifications depress insulin signaltransduction and stimulation of glucose transport, glycogensynthesis, glucose oxidation, and nonoxidized glycolysis.

CHARACTERISTICS OF MYOTUBES RAISEDIN CULTURE FROM SEVERELY OBESE INDIVIDUALS

Satellite cells from muscle biopsy samples can be culturedinto myoblasts and, subsequently, myotubes that closely re-semble mature muscle fibers. In this preparation, the influenceof factors such as neural input, hormonal concentrations, andphysical activity level on metabolic characteristics essentiallyare removed because of the length and nature of the pro-liferation and differentiation phases; findings obtained in hu-man skeletal muscle cells (HSkMC) raised in culture are thusthought to reflect a phenotype resulting from a specific DNAsequence (i.e., genetic) and/or from changes to the genomethat do not involve a change in the nucleotide sequence(i.e., epigenetic). We initiated studies with the intent ofdetermining if characteristics evident in vivo and in vitro wereretained in HSkMC with severe obesity. This model alsopermitted experimental manipulation of variables to discerncellular mechanisms that could not be accomplished in in-

tact humans.

Fat Metabolism

Our initial experiments were designed to determine if thedecrement we reported in FAO (3,27,29) was retained inHSkMC. As presented in Figure 1, the magnitude of thereduction in FAO with severe obesity virtually was identicalin HSkMC compared with intact muscle strips or muscle ho-mogenates (2,3,11,26). In addition, an index of oxidationefficiency (incomplete oxidation divided by complete oxida-tion) was similar between HSkMC and in vitro measurementsin skeletal muscles (2,3,11,26). Indices indicating increasedlipid partitioning toward storage (i.e., 14C incorporation intotriacylglycerol, phospholipids, and diacylglycerol) also were

approximate and even slightly elevated in HSkMC (2,3,11,26).These findings indicate that the metabolic signature evidentin skeletal muscles of severely obese individuals in relation toFAO is maintained in HSkMC (Fig. 1).

Gene arrays and polymerase chain reaction (PCR) analysesindicated multiple differences in gene expression with severeobesity, with one of the more pronounced being a twofoldelevation in stearoyl-CoA desaturase 1 (SCD-1) expression;this elevation in SCD-1 mRNA content also was evident inHSkMC (26). SCD-1 is a lipogenic enzyme that directs

palmitoyl-CoA (C16:0) and stearoyl-CoA (C 18:0) towardlipid synthesis but has no readily discernible effects on FAO.To mimic the severely obese state, we overexpressed SCD-1in HSkMC from lean subjects. This treatment elicited areduction in FAO and concomitantly increased lipid storage,both of which are characteristics of HSkMC from severelyobese individuals (26). The fact that both FAO and lipid

storage were altered with overexpression suggests that SCD-1may impart a multitiered level of control, with the ultimateresult of lipid accumulation.

In terms of other cellular mechanisms, there are conflictingfindings of whether a reduction in mitochondrial content or adecrement in mitochondrial function is responsible for thelower FAO evident with obesity. In HSkMC from severelyobese donors, mitochondrial content, as determined by mito-chondrial DNA copy number (mtDNA) and cytochrome coxidase IV (COX-IV) protein content, was reduced sig-nificantly (11). However, FAO was equivalent between leanand obese individuals after correcting for these indices ofmitochondrial content (i.e., FAO/mtDNA; FAO/COX-IV)(11). These data suggest that the mitochondria of severelyobese individuals function normally and that the overallreduction in FAO can be attributed primarily to a reductionin mitochondrial content (11).

To examine if skeletal muscles from severely obese indi-viduals are resistant to stimuli for mitochondrial biogenesis,PGC-1>, a transcriptional coactivator that stimulates mito-chondrial biogenesis, was overexpressed in HSkMC (11).This manipulation increased mitochondrial content andFAO in myotubes from severely obese individuals; however,FAO remained depressed compared with that in lean controls,which suggests that the severely obese state limits both mito-chondrial biogenesis and oxidative capacity via mechanismsthat are independent of PGC-1> abundance (11). Together,these data obtained in HSkMC (11,26) suggest that lipidoxidation is reduced inherently in skeletal muscles of severely

obese individuals because of impairments at several levels oflipid metabolism (i.e., increase SCD-1 expression, reducedmitochondrial content).

Insulin Action

We questioned whether the insulin resistance and changesin insulin signal transduction that we observed in muscle tissuebiopsies and in in vitro incubated muscle fiber strips of se-verely obese individuals would extend into primary cell culture.Insulin stimulation of IRS-1 tyrosine phosphorylation andAkt phosphorylation, both of which would increase signaltransduction, were blunted significantly in HSkMC fromseverely obese patients (2,5). This blunting of insulin-stimulated IRS-1 tyrosine phosphorylation in muscle fiber

strips of severely obese individuals was approximately 60%compared with that in lean controls and was reproducedessentially in HSkMC, whereas the degree of blunting of Aktactivation was even greater in HSkMC than in intact mus-cles (2,5,8,19).

As mentioned in a previous section, IRS-1 becomes serinephosphorylated in insulin-resistant muscles, which inhibitsdownstream signaling. Therefore, serine 312 phospho-IRS-1can be a useful marker of insulin resistance. Muscle serine312-phospho-IRS-1 was elevated in both intact tissue biopsies

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and in HSkMC from severely obese subjects, compared withthat in lean controls (Fig. 2). These data suggest that there areconstitutive changes in insulin signaling in skeletal muscles ofseverely obese patients that are retained in HSkMC raised inculture.

THE IMPACT OF LIPID EXPOSURE ON THEMETABOLIC PROGRAM

A high-fat, energy-rich diet likely is one of the primaryfactors contributing to the development of obesity and ec-topic lipid accumulation. However, there is evidence thatlean and obese individuals differ with respect to their abilityto increase fatty acid oxidation in the face of an increasedlipid load that can, in turn, influence the magnitude of pos-itive lipid balance. Lipid alone also appears to be detrimentalbecause relatively acute exposures can inhibit processes suchas insulin signal transduction in skeletal muscles. As theeffects of lipid exposure are encompassing and relevant to theobese condition, we have examined the ability of lipid ex-

posure to increase FAO and induce insulin resistance in leanand severely obese individuals.

Fat Metabolism

Metabolic flexibility is defined as the ability to adjust fuelutilization with respect to fuel availability. The capacity formetabolic flexibility is an important trait in the free-livingenvironment, as not responding appropriately to dietary lipidor temporary excursions where dietary lipid is elevated couldresult in positive lipid balance and accumulation.

To examine metabolic flexibility, HSkMC from lean andseverely obese subjects were incubated with a fatty acid mix-ture (palmitate:oleate) for 24 h and FAO determined withhigh-resolution respirometry (7). State 3 (adenosine diphosphateY

stimulated) respiration with lipid (palmitate) as the substrate in-creased after the 24-h lipid exposure in HSkMC from leansubjects, reflecting metabolic flexibility. This increase in FAOwas accompanied by an elevation in mtDNA and a trend for

an increase in COX-IV protein content, both of which sug-gest that mitochondrial content increased (7). In contrast,there were no comparable responses to increased lipid pres-ence in HSkMC from severely obese individuals (7). Thesefindings suggest an impaired capacity for metabolic flexibil-ity in response to lipid in skeletal muscles of severely obeseindividuals.

To gauge the capacity for metabolic flexibility in responseto dietary lipid, we placed lean and severely obese individualson a 5-d high-fat diet ((HFD) 65% of total energy from fat)and examined the responsiveness of genes controlling FAOand mitochondrial content in skeletal muscles (6). The mRNAcontent for peroxisome proliferatorYactivated receptorY>(PPAR->), a broad transcriptional regulator that up-regulatesFAO, increased in lean subjects after a single high-fat meal;in contrast, there was no change in PPAR-> expression inseverely obese subjects (6). After the 5-d HFD, PPAR-> andthe expression of other genes linked with enhancing lipidoxidation (PDK4, PGC-1>) increased in the lean subjects;however, we observed no concomitant changes in gene ex-pression in muscles of severely obese individuals (6). Withthe HFD, acylcarnitine derivatives from long-chain fattyacids were not altered, indicating no adaptation at the levelof CPT-1 in either the lean or severely obese individuals.However, shorter chain acylcarnitine (6Y12 carbons) speciesdecreased in the lean subjects with the HFD, suggestive of anincrease in FAO. These findings (6,7) indicate an inabilityto increase FAO in skeletal muscles in response to lipidexposure with severe obesity. This impairment may be anunderlying defect contributing to the lower mitochondrialcontent evident with severe obesity as muscles are subjectedconstantly to elevated lipid concentrations during normalactivities such as an overnight fast and dietary fat con-sumption. An inability to increase FAO appropriately withlipid exposure also results in a positive lipid balance, whichmay predispose an individual to weight gain. This lack of

metabolic flexibility may thus be a critical component of themetabolic program evident with severe obesity.

Insulin Action

Muscle cells in culture are an excellent tool to investigatethe mechanisms of insulin resistance. We have been inter-ested in what treatments might cause insulin resistance inHSkMC from lean individuals and how we might reverse theinsulin resistance in cells of severely obese subjects. BecauseHFD cause insulin resistance in skeletal muscles, we inves-tigated the effects of incubating HSkMC from lean and se-verely obese subjects in fatty acids for 12 to 48 h. Consistentwith our hypothesis, fatty acids caused insulin resistance in

HSkMC from lean controls, increased IRS-1 serine 312phosphorylation, and decreased insulin-stimulated IRS-1tyrosine phosphorylation and Akt activation in cells from leancontrols to values approximating those in myotubes fromseverely obese subjects (5). Because cells from severely obesesubjects were already insulin resistant, there was no furthereffect of fatty acid incubation.

Activation of adenosine monophosphate kinase (AMPK)is known to reverse insulin resistance in animal models, andmetformin may increase insulin sensitivity in humans through

Figure 2. Serine 312 phospho-IRS-1 in muscle biopsies and in primaryhuman skeletal muscle cell (HSkMC) cultures from severely obese and leancontrol subjects. Values are expressed as a percentage of the lean controlmuscle analyzed under identical conditions with dotted line at 100% indi-cating lean control. FFA, fatty free acids; IRS-1, insulin receptor substrate 1.




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this mechanism. Therefore, we tested whether activation ofAMPK could reverse insulin resistance in HSkMC from se-verely obese individuals. AICAR (an activator of AMPK)incubation rescued insulin signal transduction in HSkMCfrom severely obese subjects or cells from lean controls treatedwith fatty acids (5). These results suggest that treatment ofinsulin-sensitive skeletal muscles with fatty acids induces

insulin resistance to a degree equivalent to HSkMC fromseverely obese subjects. Likewise, insulin resistance caused byeither fatty acid treatment or severe obesity can be reversedthrough the activation of AMPK.

CAN THE METABOLIC PROGRAM OF SEVEREOBESITY BE EFFECTIVELY TREATED?

If our obesity metabolic program hypothesis is correct, arelated question is whether the program can be turned offand metabolism can be returned to values similar to those inlean individuals. Two interventions that were available for usto test this question were weight loss induced by gastric bypass

surgery and physical activity.

Fat Metabolism and Weight Loss

When examining the decrement in FAO with severe obe-sity, the classic chicken-or-egg question arises, that is, isFAO impaired before developing severe obesity and thuspossibly contribute to weight gain or does the reduction inFAO develop as a consequence of being severely obese? Oneway of addressing this issue was using the HSkMC model asalready discussed. However, another approach is to reversethe condition of severe obesity to the preseverely obese stateand determine if FAO is, in turn, normalized. From a clinicalperspective, it also is important to examine the effectivenessof weight loss in addressing the deficits in metabolism evident

with severe obesity.To determine if weight loss normalizes FAO, Berggren et al.

(3) compared FAO in severely obese women who were weightstable for 1 yr or longer after gastric bypass surgery with thosein lean controls and severely obese individuals. FAO inskeletal muscles (vastus lateralis) did not differ between thegastric bypass surgery/weight loss (BMI, 36.5 T 3.5 kgImY2) andseverely obese (50.7 T 3.9 kgImj2) groups and was depressedcompared with that in the lean (22.8 T 1.2 kgImY2) women.Studying individuals using a repeated-measures design beforeand approximately 1 yr after gastric bypass surgery, we alsoobserved that FAO remained depressed in women who lost55 kg to achieve a mean BMI of 30.5 T 2.3 kgImY2 (3). Tracermethodology (13C palmitate and 14C acetate) was used to

compare FAO in lean, severely obese, and postgastric bypasspatients who had lost more than 45 kg to achieve a BMI of33.7 T 9.9 kgImY2 (34). Similar to skeletal muscles, whole-body FAO was depressed in the gastric bypass/weight loss andseverely obese women both during rest and mild (50% VO2max)exercise (34). A comparison of fat utilization during sub-maximal exercise with indirect calorimetry also indicatedthat whole-body lipid oxidation was depressed in previouslyseverely obese women who had lost weight via gastric bypasssurgery compared with that in weight-matched controls (21).

Together, these observations, as summarized in Figure 1,indicate that the decrement in FAO with severe obesity re-mains evident despite pronounced weight loss and reversal ofthe severely obese state. If an impairment in FAO is linkedwith weight gain, an inability to normalize FAO with weightloss intervention may explain why some individuals are pre-disposed to weight regain after dietary interventions. In se-

verely obese individuals, the mechanical limitations imposedby the gastric bypass procedure may be the only practical andeffective intervention to ensure long-term weight loss.

Insulin Action and Weight Loss

Results from a number of laboratories have reported thatweight loss is associated with an improvement in insulin ac-tion. However, the degree of obesity and insulin resistance inthose studies was not as severe as in our patients. To testwhether weight loss after gastric bypass could reverse the in-sulin resistance of severe obesity, we studied a group of womenwho lost approximately 50 kg after surgery and were weightstable for at least 3 months (surgery/weight loss group) (4).Because the experimental subjects still had a BMI of approx-imately 30 kgImY2, the surgery/weight loss group was comparedwith 1) severely obese women, 2) weight- and age-matchedwomen who were never severely obese, and 3) age-matchedbut lean (BMI, G25 kgImY2) women. Whole-body insulinsensitivity (insulin sensitivity index (SI) determined from afrequently sampled intravenous glucose tolerance test) wasmuch lower in severely obese individuals compared with thatin the other groups (4). The SI of the surgery/weight lossgroup was not different than the lean group and was higherthan in the weight-matched women. Likewise, muscle IRS-1serine 312 phosphorylation in the surgery/weight loss groupmatched that of the lean group and significantly was lowerthan that of the severely obese or the weight-matched groups.Thus, the weight loss induced by gastric bypass not only

reverses insulin resistance but actually improves insulin sensi-tivity to a degree that is superior to that seen in weight-matched controls. This improvement in insulin action cannotbe attributed to increased physical activity after gastric bypass,which is equivalent between previously severely obese surgerypatients and weight-matched sedentary controls (21). Pro-spective studies have confirmed that gastric bypass surgerydramatically enhances insulin action in severely obesepatients (20,25).

In terms of possible mechanisms, we observed no changein the concentration of the insulin-sensitive glucose trans-porter (GLUT4) with weight loss (18). Insulin receptor con-centration, however, doubled, which may contribute to theimprovement in insulin action seen with the intervention (31).

Gene array and real-time PCR analyses indicated thatgrowth factor receptorYbound protein 14, glycerol-3-phosphatedehydrogenase, and myostatin were elevated with severe obe-sity and reduced with weight loss (30). Pathway analyses indi-cated the involvement of these genes in weight-loss responsivenetworks, which could improve insulin signaling, decrease tri-glyceride synthesis, and increase muscle mass (30). The pre-dominance of insulin-resistant glycolytic muscle fibers evidentwith severe obesity (22) was not altered with gastric bypasssurgery (20), although a higher initial percentage of Type I




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fibers was associated with a greater rate of weight reduction(33). In contrast, intramuscular triacylglycerol and long-chain fatty acyl-CoA concentrations (palmityl, stearate, andlinoleate CoA) were reduced dramatically (20,25). Thisreduction in intramuscular lipid content could contribute tothe improvement in insulin action seen with gastric bypasssurgery as intracellular lipids can induce insulin resistance.

Fat Metabolism, Insulin Action, and Exercise

Classic responses to endurance-oriented exercise traininginclude an increase in the capacity of skeletal muscles forFAO and an improvement in insulin action. Our laboratorieshave used relatively acute programs (7 Y10 consecutive days)to discern the effects of endurance-oriented exercise trainingon insulin action and FAO. This model is used because 1)there is little to no loss in body mass, thus minimizing theeffect of this potentially confounding factor, and 2) it facili-tates the recruitment and retention of populations typicallynot accustomed to exercise training. To examine the impactof exercise on insulin action, severely obese men trained for 7consecutive days (60 minIdY1, 65% VO2peak) with insulinaction determined via an oral glucose tolerance test (OGTT)in the sedentary condition and approximately 16 h after thefinal exercise bout (23). Exercise training reduced fasting and2-h insulin concentrations and the insulin area under thecurve during the OGTT, indicating improved insulin action.

A similar training prescription (10 consecutive days,60 minIdY1, 70% VO2peak) was used to examine the effect ofexercise on FAO (3). We studied previously severely obeseindividuals who had lost weight via gastric bypass surgerybecause of their ability to ambulate effectively and achieve andmaintain the desired exercise intensity. In agreement with ourprevious findings, FAO was reduced and incomplete FAO was

elevated in the gastric bypass/weight loss compared with thosein lean and a group of obese, but not severely obese, subjects.The 10 d of exercise training increased FAO by approximatelytwofold in the lean and obese groups and, despite the initialimpairment, also increased FAO in the gastric bypass/weightloss group to the extent that there was no difference betweenthe lean, obese, and weight loss groups after the intervention.

Incomplete oxidation also was normalized after exercise train-ing (3). These findings (3,23) indicate that exercise trainingcan be used to alleviate effectively the phenotype/metabolicprogram of insulin resistance and reduced FAO evident withsevere obesity, although the cellular mechanisms remain to bedefined (see Fig. 1).

CONCLUSIONS

Severe obesity (BMI, Q40 kgImY2) is associated with insu-lin resistance and a reduced capacity for fatty acid oxidationin skeletal muscles. These characteristics remain intact inHSkMC raised in culture, which has led us to hypothesizethat the skeletal muscle of severely obese individuals displaysan inherent global metabolic program (see Fig. 3). We believethat this concept represents a paradigm shift in our perceptionof obesity. For example, the deficit in FAO and inability toincrease FAO appropriately in response to ingested lipid (lackof metabolic flexibility) may predispose an individual towardectopic lipid accumulation and weight gain and possibly thedevelopment of the severely obese state. The present findingsalso indicate that the metabolic program linked with insulinresistance can be induced by fatty acid exposure.

As presented in Figure 3, weight loss via gastric bypasssurgery can turn off components of this metabolic program as

Figure 3. Summary of the metabolic program in human skeletal muscle with severe obesity in relation to fat and carbohydrate (CHO) metabolism. In thetop panel, arrows represent processes elevated or depressed compared with those in lean controls either in vivo or in in vitro muscle preparations or humanskeletal muscle cells (HSkMC) raised in culture. The lower panel represents increases, decreases, or no change compared with that of the severely obesecondition with the respective intervention.




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insulin sensitivity is restored or even enhanced comparedwith that in weight-matched controls. However, gastricbypass/weight loss does not rescue the decrement in FAO,which may explain a propensity for weight regain after or aresistance to diet-induced weight loss and why the mech-anical limitations imposed by the gastric bypass procedureare needed for an effective intervention. Endurance-oriented

exercise training can improve FAO and insulin action inseverely obese individuals, indicating that this patient pop-ulation is not exercise resistant; exercise should thus beconsidered as an adjunct to weight loss intervention. Thebiological mechanisms linked with these perturbations andinterventions are yet to be discerned largely. In conclusion, itis hoped that the research summarized in this review can aidin preventing and/or treating the severely obese condition.

Acknowledgments

This study was supported by the National Institutes of Health (J.A. Houmard,W.J. Pories, G.L. Dohm), Johnson and Johnson (W.J. Pories, G.L. Dohm),and GlaxoSmithKline (W.J. Pories, G.L. Dohm).

The authors declare no conflicts of interest.

References

1. Azevedo JL Jr, Carey JO, Pories WJ, Morris PG, Dohm GL. Hypoxiastimulates glucose transport in insulin-resistant human skeletal muscle.

Diabetes. 1995; 44:695Y8.2. Bell JA, Reed MA, Consitt LA, et al. Lipid partitioning, incomplete fatty

acid oxidation, and insulin signal transduction in primary human musclecells: Effects of severe obesity, fatty acid incubation, and fatty acidtranslocase/CD36 overexpression. J. Clin. Endocrinol. Metab. 2010; 95:3400Y10.

3. Berggren JR, Boyle KE, Chapman WH, Houmard JA. Skeletal musclelipid oxidation and obesity: Influence of weight loss and exercise. Am. J.Physiol. Endocrinol. Metab. 2008; 294:E726Y32.

4. Bikman BT, Zheng D, Pories WJ, et al. Mechanism for improved insulinsensitivity after gastric bypass surgery. J. Clin. Endocrinol. Metab. 2008;93:4656Y63.

5. Bikman BT, Zheng D, Reed MA, Hickner RC, Houmard JA, Dohm GL.Lipid-induced insulin resistance is prevented in lean and obese myotubes

by AICAR treatment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010;298:R1692Y9.

6. Boyle KE, Canham JP, Consitt LA, et al. A high-fat diet elicits differ-ential responses in genes coordinating oxidative metabolism in skeletalmuscle of lean and obese individuals. J. Clin. Endocrinol. Metab. 2011;96:775Y81.

7. Boyle KE, Zheng D, Anderson EJ, Neufer PD, Houmard JA. Mito-chondrial lipid oxidation is impaired in cultured myotubes from obesehumans. Int. J. Obes. (Lond). 2012; 36:1025Y31.

8. Brozinick JT Jr, Roberts BR, Dohm GL. Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle:Potential role in insulin resistance. Diabetes. 2003; 52:935Y41.

9. Carey JO, Azevedo JL Jr, Morris PG, Pories WJ, Dohm GL. Okadaic acid,vanadate, and phenylarsine oxide stimulate 2-deoxyglucose transport ininsulin-resistant human skeletal muscle. Diabetes. 1995; 44:682Y8.

10. Caro JF, Sinha MK, Raju SM, et al. Insulin receptor kinase in humanskeletal muscle from obese subjects with and without noninsulin de-

pendent diabetes. J. Clin. Invest. 1987; 79:1330Y

7.11. Consitt LA, Bell JA, Koves TR, et al. Peroxisome proliferatorYactivated

receptorYgamma coactivator-1alpha overexpression increases lipid oxi-dation in myocytes from extremely obese individuals. Diabetes. 2010;59:1407Y15.

12. Cortright RN, Azevedo JL Jr, Zhou Q, et al. Protein kinase C modulatesinsulin action in human skeletal muscle. Am. J. Physiol. Endocrinol.Metab. 2000; 278:E553Y62.

13. Dohm GL, Elton CW, Raju MS, et al. IGF-IYstimulated glucose transportin human skeletal muscle and IGF-I resistance in obesity and NIDDM.

Diabetes. 1990; 39:1028Y32.

14. Dohm GL, Tapscott EB, Pories WJ, et al. An in vitro human musclepreparation suitable for metabolic studies. Decreased insulin stimulationof glucose transport in muscle from morbidly obese and diabetic subjects.

J. Clin. Invest. 1988; 82:486Y94.15. Dolan PL, Tapscott EB, Dorton PJ, Dohm GL. Contractile activity

restores insulin responsiveness in skeletal muscle of obese Zucker rats.

Biochem. J. 1993; 289(pt 2):423Y6.16. Elton CW, Tapscott EB, Pories WJ, Dohm GL. Effect of moderate

obesity on glucose transport in human muscle. Horm. Metab. Res. 1994;

26:181Y

3.17. Friedman JE, Caro JF, Pories WJ, Azevedo JL Jr, Dohm GL. Glucose

metabolism in incubated human muscle: Effect of obesity and non-insulin-dependent diabetes mellitus. Metabolism. 1994; 43:1047Y54.

18. Friedman JE, Dohm GL, Leggett-Frazier N, et al. Restoration of insulinresponsiveness in skeletal muscle of morbidly obese patients after weightloss. Effect on muscle glucose transport and glucose transporter GLUT4.

J. Clin. Invest. 1992; 89:701Y5.19. Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL.

Insulin receptor phosphorylation, insulin receptor substrate-1 phos-phorylation, and phosphatidylinositol 3-kinase activity are decreasedin intact skeletal muscle strips from obese subjects. J. Clin. Invest. 1995;95:2195Y204.

20. Gray RE, Tanner CJ, Pories WJ, MacDonald KG, Houmard JA. Effect ofweight loss on muscle lipid content in morbidly obese subjects. Am. J.Physiol. Endocrinol. Metab. 2003; 284:E726Y32.

21. Guesbeck NR, Hickey MS, MacDonald KG, et al. Substrate utilization

during exercise in formerly morbidly obese women. J. Appl. Physiol. 2001;90:1007Y12.22. Hickey MS, Carey JO, Azevedo JL, et al. Skeletal muscle fiber composi-

tion is related to adiposity and in vitro glucose transport rate in humans.

Am. J. Physiol. 1995; 268:E453Y7.23. Hickey MS, Gavingan KE, McCammon MR, et al. Effects of 7 days of

exercise training on insulin action in morbidly obese men. Clin. Exerc.Physiol. 1999; 1:24Y8.

24. Hittel DS, Hathout Y, Hoffman EP, Houmard JA. Proteome analysis ofskeletal muscle from obese and morbidly obese women. Diabetes. 2005;54:1283Y8.

25. Houmard JA, Tanner CJ, Yu C, et al. Effect of weight loss on insulinsensitivity and intramuscular long-chain fatty acyl-CoAs in morbidlyobese subjects. Diabetes. 2002; 51:2959Y63.

26. Hulver MW, Berggren JR, Carper MJ, et al. Elevated stearoyl-CoAdesaturase-1 expression in skeletal muscle contributes to abnormal fattyacid partitioning in obese humans. Cell Metab. 2005; 2:251Y61.

27. Hulver MW, Berggren JR, Cortright RN, et al. Skeletal muscle lipidmetabolism with obesity. Am. J. Physiol. Endocrinol. Metab. 2003; 284:E741Y7.

28. Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL. Involvement ofprotein kinase C in human skeletal muscle insulin resistance and obesity.Diabetes. 2000; 49:1353Y8.

29. Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA. Lipidoxidation is reduced in obese human skeletal muscle. Am. J. Physiol.Endocrinol. Metab. 2000; 279:E1039Y44.

30. Park JJ, Berggren JR, Hulver MW, Houmard JA, Hoffman EP. GRB14,GPD1, and GDF8 as potential network collaborators in weight lossYinduced improvements in insulin action in human skeletal muscle.Physiol. Genomics. 2006; 27:114Y21.

31. Pender C, Goldfine ID, Tanner CJ, et al. Muscle insulin receptorconcentrations in obese patients post bariatric surgery: Relationshipto hyperinsulinemia. Int. J. Obes. Relat. Metab. Disord. 2004; 28:363Y9.

32. Reed MA, Pories WJ, Chapman W, et al. Roux-en-Y gastric bypass cor-

rects hyperinsulinemia implications for the remission of type 2 diabetes. J.Clin. Endocrinol. Metab. 2011; 96:2525Y31.

33. Tanner CJ, Barakat HA, Dohm GL, et al. Muscle fiber type is associatedwith obesity and weight loss. Am. J. Physiol. Endocrinol. Metab. 2002;282:E1191Y6.

34. Thyfault JP, Kraus RM, Hickner RC, Howell AW, Wolfe RR, Do hm GL .Impaired plasma fatty acid oxidation in extremely obese women.

Am. J. Physi ol. Endoc rinol . Metab . 2004; 287:E1076Y81.35. Zhou Q, Dolan PL, Dohm GL. Dephosphorylation increases insulin-

stimulated receptor kinase activity in skeletal muscle of obese Zuckerrats. Mol. Cell. Biochem. 1999; 194:209Y16.


Severe Obesity Evidence for a Deranged Metabolic

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